The β-lactam ring (Hoten & Onusko (2000) Am. Family Physician 62:611-620) is part of the structure of several antibiotic families, principally the penicillin derivatives, cephalosporins and related compounds, which are therefore also called β-lactam antibiotics (Gilchrist (1997) Heterocyclic Chemistry Harlow: Longman). As a group, these drugs are active against many gram-positive, gram-negative and anaerobic organisms. These antibiotics work by inhibiting the bacterial cell wall synthesis (Levy (1992) The Antibiotics Paradox Plenum Press: New York). This has a lethal effect on bacteria.
The discovery of antibiotics that can be used systemically is the most important medical event in the twentieth century. The story of the discovery by Sir Alexander Fleming of the penicillins in 1929 is well-known (Fleming (1929) Br. J. Exp. Pathol. 10:226-230). The introduction of penicillin into clinical trials in 1941 was followed in short order by the discovery of a plethora of penicillins and cephalosporins, streptomycin (Waksman, et al. (1946) J. Bacteriol. 52:393-7), chloramphenicol (Lagodsky, (1951) Biol. Med. (Paris) 40:2-81), tetracycline (Finland (1974) Clin. Pharmacol. Ther. 15:3-8), and erythromycin (McGuire, et al. (1952) Antimicrob. Chemother. 2:281-283). However, shortly after the clinical introduction of antibiotics, reports of microbial resistance during the course of treatment began to appear in the literature. Penicillin was first used in 1941, and by 1942 publications relating to resistance appeared (Remmelkamp & Kamp (1942) Proc. Soc. Exptl. Biol. Med. 51:356-360). Resistance was noted with increasing frequency until this phenomenon could no longer be ignored (Mitscher (2008) J. Nat. Prod. 71:497-509). Societal impact of antibiotic resistance is a major public health problem (Metlay, et al. (2002) J. Gen. Inter. Med. 17:87-94). To avoid the development of antibiotic resistance, newer antibiotics should be reserved for patients infected with resistant bacteria.
Effective strategies to deal with the resistance problem are relatively few. On approach includes the use of a combination therapy such as meropenem and clavulanate, which has been shown to kill replicating and non-replicating Mycobacterium tuberculosis (Hugonnet, et al. (2009) Science 323:1215-8). Other strategies include searching for novel antibiotics, modification of existing antibiotics, synthesis and directed biosynthesis of novel antimicrobials, inhibition of bacterial enzymes that inactivate antibiotics, use of combinations of antibiotics, immunostimulants, and the identification of new targets for antibiotics. This effort subsequently led to combinatorial methods for synthesis of analogs of β-lactams (Frank, et al. (1998) Comb. Chem. High-Throughput Screen. 1:56-70; Kline, et al. (2000) Bioorgn. Med. Chem. 8:73-93), which have a number of targets, many of which are not related to peptidoglycan biosynthesis and many of which are found in eukaryotic cells (Veinberg, et al. (2013) Curr. Med. Chem. Vol. 20).
The availability of 6-aminopenicillanic acid (6-APA, 1; Batchelor, et al. (1959) Nature 183:257; Sheehan & Henery-Logan (1959) J. Am. Chem. Soc. 81:5838) has made possible the synthesis of new, improved penicillins when covalently linked to a side-chain moiety.
The cephalosporin nucleus, 7-aminodesacetoxy cephalosporanic acid (7-ADCA, 2; Archer & Kitchell (1966) J. Org. Chem. 31:3409-11), was derived from cephalosporin C and is an analog of the penicillin nucleus 6-APA. Modification of the 7-ADCA side-chains could also result in the development of useful antibiotic agents.
